This proposal is designed to test an improved gene delivery strategy for the treatment of age-related macular degeneration (AMD). Wet AMD and diabetic retinopathy are the most common causes of blindness in the developed world. Both diseases are caused by the abnormal growth of blood vessels in the eye. Current treatments that destroy or inhibit the growth of existing blood vessels can delay vision loss but do not affect the underlying disease and neovascularization is a recurring problem. Pigmented epithelial derived factor (PEDF) is a potent anti-angiogenic and neuroprotective protein that is naturally produced in the eye. When delivered to the eye via an adenovirus vector, PEDF can block growth of new blood vessels and trigger the regression of established abnormal vessels in animal models for AMD and diabetic retinopathy. GenVec has recently commenced a Phase I clinical trial to access the safety of delivering PEDF to the eye with an E1/E3/E4-deleted adenovector in patients with AMD. Preclinical data for this vector indicates a very good efficacy and safety profile. However, two important risks to the commercialization of AdPEDF are the potential for vector induced inflammation and transient PEDF expression, both of which have been observed in animal models. We propose to evaluate a new and improved adenovector for toxicity and stable PEDF expression in the eye. High-capacity (HC) vectors, also termed gutless, gutted and helper-dependent adenovectors do not contain or express any adenovirus genes. In other tissues, HC vectors have been shown to be less toxic and less immunogenic than first- and second-generation adenovirus vectors. In addition, long-term transgene expression has been observed with these vectors in various tissues including the eye. Our proposal for this SBIR Phase I grant is to test the hypothesis that HC adenovectors will bring about persistent transgene expression with reduced inflammation relative to second-generation adenovirus vectors following intravitreous delivery to the mouse eye. Phase 2 will focus on demonstrating better efficacy and testing toxicity in vivo models of AMD. In addition, we will develop a regulated system for PEDF expression from a HC vector and begin to implement a manufacturing strategy for clinical grade HC vectors. The long-term goal is clinical testing and commercialization a PEDF expressing HC vector.